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CHAPTER 5 Pharmacogenomics 85

ximelagatran is associated with a HLA-DRB1*07:01 allele. Several exemplified by warfarin, where the effects of two genes, CYP2C9 and
drugs used in the treatment of tuberculosis, including isoniazid, VKORC1, on dose requirement have been clearly defined.
rifampin, and ethambutol, also cause liver injury, which appears
to be related to HLA polymorphisms.
CYP2C9 & VKORC1
IFNL3 (IL-28B) CYP2C9 is a phase I drug-metabolizing enzyme that acts primar-

Interferon lambda-3 (IFN-λ3; also known as interleukin-28B), ily on acidic drugs including S-warfarin, phenytoin, and NSAIDs
encoded by the IFNL3 (or IL28B) gene, belongs to the family of (Chapter 4). The gene that encodes CYP2C9 is highly polymor-
type III IFN-λ cytokines. Type III IFNs share many therapeutic phic, with over 50 alleles defined (www.cypalleles.ki.se/cyp2c9.
effects with type I IFNs, eg, IFN-a (Chapter 55), such as being htm). However, much of the variability in metabolic clearance
directly induced by viruses and acting through JAK-STAT signal of CYP2C9 substrates may be accounted for with just two well-
transduction pathways (via distinct heterodimeric receptor signal- studied alleles, CYP2C9*2 and *3. Allele CYP2C9*2 encodes an
ing complexes) to produce antiviral activity in cells. Type III IFNs amino acid change (Arg144Cys) located on the outer surface of
play a role in hepatitis C virus (HCV) infection. Genetic variants the CYP2C9 enzyme, which impairs interaction with the micro-
near the IFNL3 gene were found to be most significantly associated somal P450 oxidoreductase and leads to reduced metabolism of
with HCV treatment response to pegylated-IFN-a (PEG-IFN-a), CYP2C9 substrates, including a 30–40% reduction in S-warfarin
in combination with ribavirin (RBV). Approximately twofold metabolism. Allele CYP2C9*3 encodes an amino acid change (Ile-
greater cure rates were observed in patients with a favorable geno- 359Leu) on the interior of the enzyme, which results in lowered
type. While the mechanism underlying this association has yet to be affinity for many CYP2C9 substrates and a more marked (80–
fully elucidated, the rs12979860 variant near IFNL3 is considered 90%) reduction in S-warfarin metabolism. Both alleles *2 and *3
the strongest baseline predictor of a cure for patients with HCV-1 are more common in European populations compared with Afri-
receiving PEG-IFN-a/RBV. The favorable allele, the rs12979860 can and Asian populations (7–13% vs < 5%, respectively) and are
variant, is inherited most frequently in Asians (∼90%), and least therefore most useful to explain CYP2C9 variability in Europeans
frequently in Africans (Table 5–1). This frequency distribution is (Table 5–1). Additional reduced function alleles, eg, CYP2C9*5,
remarkably similar to rates of response to HCV PEG-IFN-a/RBV
treatment among the three ethnic groups. *6, *8, and *11, occur more frequently in African populations,
Pegylated interferon with ribavirin: Chronic HCV affects and as evidence accumulates, their inclusion in genetic tests may
160 million people worldwide and is a leading cause of cirrhosis improve our ability to explain warfarin variability in Africans.
of the liver and liver cancer. The goal for HCV antiviral therapy Vitamin K epoxide reductase complex subunit 1 (VKORC1),
is to resolve the infection, defined clinically as achievement of encoded by the VKORC1 gene, is the target of anticoagulant
sustained virologic response (SVR), ie, undetectable HCV RNA warfarin and a key enzyme in the vitamin K recycling process
measured 6 months after finishing treatment. For patients receiv- (Chapter 34, Figure 34–6). Activated vitamin K is an essential
ing PEG-IFN-a/RBV regimens, which are associated with many cofactor for activation of blood clotting factors II, VII, IX, and
side effects and poor response, clinical decisions of whether to X, as well as endogenous anticoagulant proteins C and S. Rare
initiate therapy are largely based on likelihood of SVR. Predic- genetic variants in the coding region of VKORC1 may lead to
tors of SVR include viral factors, as well as patient factors. In bleeding disorders, eg, multiple coagulation factor deficiency
addition, Europeans homozygous for the favorable genotype type 2A, or warfarin resistance. A polymorphism common across
(IFNL3 rs12979860/rs12979860; SVR: 69%) are more likely to all major ethnicities is located in a transcription factor-binding
achieve SVR compared with the unfavorable genotype (IFNL3 site, VKORC1-1639G>A, which results in reduced expression
reference/reference or reference/rs12979860; SVR: 33% and 27%, of VKORC1 in the liver. The most important consequences of
respectively), and similar rates are observed in African patients. the VKORC1 polymorphism are increased sensitivity to warfarin
Guidelines according to CPIC are shown in Table 5–2. (discussed below). The VKORC1-1639G>A polymorphism occurs
most frequently in Asian populations (∼90%) and least often in
Africans (∼10%), which explains, in part, the difference in dosing
■ POLYGENIC EFFECTS requirements among major ethnic groups (Table 5–1).
Example: Warfarin, a vitamin K antagonist, is the oldest and
In the above examples, variations within single gene loci are described most widely prescribed oral anticoagulant worldwide. Within a
that are significantly associated with altered drug response or toxicity. narrow therapeutic range, warfarin is highly effective for the pre-
However, it is expected that polygenic influences, ie, the combinato- vention and treatment of thromboembolic disorders (Chapter 34).
rial effect of multiple genes on drug response, may more accurately Nevertheless, interpatient differences in dosing requirements
describe individual differences with respect to clinical outcomes. (up to 20-fold) often lead to complications from subtherapeutic
As evidence grows linking newly discovered pharmacogenetic bio- anticoagulation and clotting or supratherapeutic anticoagulation
markers with therapeutic response or adverse outcomes, adequately and bleeding, which are among the most common causes for
powered clinical studies that consider the impact of newly discovered emergency room visits in the United States. Understanding the
genes in the context of previously established genetic biomarkers are factors that contribute to variability in individual warfarin main-
essential for making strong clinical recommendations. This is best tenance doses may improve therapeutic outcomes.